The papillomaviruses cause benign and malignant lesions of squamous epithelia in higher vertebrates. The complete lytic cycle of these viruses (including late gene expression) occurs only in the differentiated cells of the squamous epithelium. Malignant lesions and infected cells in culture do not produce virus. An understanding of the transcriptional regulation of the papilloma- viruses and its relationship to the control of epithelial cell differentiation is necessary for the elucidation of the role of the papillomaviruses in carcinogenesis. We have used bovine papillomavirus type 1 (BPV-1) as a model system for the study of late transcription and its control. BPV-1 transcription in productively infected tissue has been mapped by a combination of cDNA cloning, nuclease S1 protection, and primer extension and compared to similar analyses for BPV-1 fibroma tissue and BPV-1- transformed C127 cells. A strong viral transcriptional promoter (called the late promoter) has been identified which is active only in productively infected epithelium. All other viral promoters are active in both the fibropapilloma and in BPV-1-transformed cells. We are currently attempting to identify the cis- and trans-acting elements which are involved in the control of the late promoter and to determine the role which these trans-acting factors may play in epithelial cell differentiation. Control of late transcription is also mediated through cis-acting elements in the late region. These elements most likely function through transcription termination, polyadenylation, and/or mRNA destabilization. One element has been identified which decreases gene expression when placed upstream of the polyadenylation site in a eukaryotic expression vector. Additional cis-acting element are being mapped and their mechanisms of action determined. Viral and/or cellular factors which interact in trans with these elements will also be identified.